title: Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma?
abstract: OBJECTIVE
  Because aberrant Wnt signaling has been linked with systemic sclerosis (SSc) and pulmonary fibrosis, we sought to investigate the effect of Wnt-10b on skin homeostasis and differentiation in transgenic mice and in explanted mesenchymal cells.
  
  
  METHODS
  The expression of Wnt-10b in patients with SSc and in a mouse model of fibrosis was investigated. The skin phenotype and biochemical characteristics of Wnt-10b-transgenic mice were evaluated. The in vitro effects of ectopic Wnt-10b were examined in explanted skin fibroblasts and preadipocytes.
  
  
  RESULTS
  The expression of Wnt-10b was increased in lesional skin biopsy specimens from patients with SSc and in those obtained from mice with bleomycin-induced fibrosis. Transgenic mice expressing Wnt-10b showed progressive loss of subcutaneous adipose tissue accompanied by dermal fibrosis, increased collagen deposition, fibroblast activation, and myofibroblast accumulation. Wnt activity correlated with collagen gene expression in these biopsy specimens. Explanted skin fibroblasts from transgenic mice demonstrated persistent Wnt/β-catenin signaling and elevated collagen and α-smooth muscle actin gene expression. Wnt-10b infection of normal fibroblasts and preadipocytes resulted in blockade of adipogenesis and transforming growth factor β (TGFβ)-independent up-regulation of fibrotic gene expression.
  
  
  CONCLUSIONS
  SSc is associated with increased Wnt-10b expression in the skin. Ectopic Wnt-10b causes loss of subcutaneous adipose tissue and TGFβ-independent dermal fibrosis in transgenic mice. These findings suggest that Wnt-10b switches differentiation of mesenchymal cells toward myofibroblasts by inducing a fibrogenic transcriptional program while suppressing adipogenesis. Wnt-10b-transgenic mice represent a novel animal model for investigating Wnt signaling in the setting of fibrosis.
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Denisa
authors.initials: D
authors.lastname: Melichian
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Komura
authors.forename: Monique
authors.initials: M
authors.lastname: Hinchcliff
authors.forename: Anna P
authors.initials: AP
authors.lastname: Lam
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Gottardi
authors.forename: Ormond A
authors.initials: OA
authors.lastname: MacDougald
authors.forename: John
authors.initials: J
authors.lastname: Varga
mesh_terms: D000199:Actins / Q000096:biosynthesis; D050156:Adipogenesis; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D018929:Cell Culture Techniques; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D008060:Lipodystrophy / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D012867:Skin / Q000378:metabolism* / Q000473:pathology*; D051153:Wnt Proteins / Q000096:biosynthesis*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D051153:Wnt Proteins; C102068:Wnt10b protein, mouse; C544013:alpha-smooth muscle actin, mouse; D051176:beta Catenin; D001761:Bleomycin; D003094:Collagen